Although a mouse model has widely been used to study the immune system of mammals, it is not an ideal experimental model for understanding the human immune system as there is a considerable gap between the immune systems of mice and humans. This gap includes the expression of CD1b and CD1c molecules; the gene and the protein expression of these group I CD1 molecules are present in humans but absent in mice. These CD1 molecules are important molecules that can present antigens containing lipid moiety and stimulate human T cells in vitro. Therefore, we created "humanized" mice that express CD1b and CD1c molecules. This was done by generating human CD1b/c-transgenic mice using Bacterial Artificial Chromosome (BAC) technology, and then crossing the CD1b/c-BAC-transgenic mice to human beta2-microglobulin-transgenic mice. This BAC technology allows for the generation of mice carrying large fragments of foreign genomic DNA and, therefore, expressing transgenes in a faithful manner. In fact, we found that the expression patterns of these CD1 molecules by different cell types in our humanized mice are very much similar to those reported in humans as determined by a flow cytometric assay and by immunohistochemistry. Interestingly, most of the antigens, which are known to bind to CD1b/c molecules and activate human T cells in vitro, are lipids derived from Mycobacterium tuberculosis. M. tuberculosis, a majority of which is composed of lipids, is a cause of one of the most important emerging infectious diseases worldwide, and also a potential bioterrorism agent. Therefore, the successful generation of the human CD1b/c-transgenic mice will permit us to study the following Aims: Specific Aim 1: Determine the nature of newly generated CD1-mediated immunity in human CD1b/c transgenic mice. Specific Aim 2: Determine the protective role of the CD1-mediated immunity against mycobacteria, whose lipid components are known to bind to CD1b/c and activate human T cells.